科研之友
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摘要
ATP-regulated potassium (K-ATP) channel complexes of inward rectifier potassium channel (K-ir) 6.2 and sulfonylurea receptor (SUR) 1 critically regulate pancreatic islet beta-cell membrane potential, calcium influx, and insulin secretion, and consequently, represent important drug targets for metabolic disorders of glucose homeostasis. The K-ATP channel opener diazoxide is used clinically to treat intractable hypoglycemia caused by excessive insulin secretion, but its use is limited by off-target effects due to lack of potency and selectivity. Some progress has been made in developing improved K(ir)6.2/SUR1 agonists from existing chemical scaffolds and compound screening, but there are surprisingly few distinct chemotypes that are specific for SUR1-containing K-ATP channels. Here we report the serendipitous discovery in a high-throughput screen of a novel activator of K(ir)6.2/SUR1:VU0071063 [7-(4-(tert-butyl)benzyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione]. The xanthine derivative rapidly and dose-dependently activates K(ir)6.2/SUR1 with a half-effective concentration (EC50) of approximately 7 mu M, is more efficacious than diazoxide at low micromolar concentrations, directly activates the channel in excised membrane patches, and is selective for SUR1-over SUR2A-containing K(ir)6.1 or K(ir)6.2 channels, as well as K(ir)2.1, K(ir)2.2, K(ir)2.3, K(ir)3.1/3.2, and voltage-gated potassium channel 2.1. Finally, we show that VU0071063 activates native K(ir)6.2/SUR1 channels, thereby inhibiting glucose-stimulated calcium entry in isolated mouse pancreatic beta cells. VU0071063 represents a novel tool/compound for investigating beta-cell physiology, K-ATP channel gating, and a new chemical scaffold for developing improved activators with medicinal chemistry.
- 出版日期2014-6
